Intake of hemoglobin by the hemoglobin-haptoglobin receptor CD163 leads to a distinct alternative non-foam cell antiinflammatory macrophage phenotype that was previously considered atheroprotective. Here, we reveal an unexpected but important pathogenic role for these macrophages in atherosclerosis. Using human atherosclerotic samples, cultured cells, and a mouse model of advanced atherosclerosis, we investigated the role of intraplaque hemorrhage on macrophage function with respect to angiogenesis, vascular permeability, inflammation, and plaque progression. In human atherosclerotic lesions, CD163+ macrophages were associated with plaque progression, microvascularity, and a high level of HIF1α and VEGF-A expression. We observed irregular vascular endothelial cadherin in intraplaque microvessels surrounded by CD163+ macrophages. Within these cells, activation of HIF1α via inhibition of prolyl hydroxylases promoted VEGF-mediated increases in intraplaque angiogenesis, vascular permeability, and inflammatory cell recruitment. CD163+ macrophages increased intraplaque endothelial VCAM expression and plaque inflammation. Subjects with homozygous minor alleles of the SNP rs7136716 had elevated microvessel density, increased expression of CD163 in ruptured coronary plaques, and a higher risk of myocardial infarction and coronary heart disease in population cohorts. Thus, our findings highlight a nonlipid-driven mechanism by which alternative macrophages promote plaque angiogenesis, leakiness, inflammation, and progression via the CD163/HIF1α/VEGF-A pathway.
Coronavirus disease 2019 (Covid-19) is associated with high incidence of venous and arterial thromboembolic events. Currently, there are no markers to guide antithrombotic therapy in Covid-19. Immature platelets represent a population of hyper-reactive platelets associated with arterial events. This prospective study compared consecutive Covid-19 patients (n = 47, median age = 56 years) to patients with acute myocardial infarction (AMI, n = 100, median age = 59 years) and a group of stable patients with cardiovascular risk factors (n = 64, median age = 68 years). Immature platelet fraction (IPF) and immature platelet count (IPC) were determined by the Sysmex XN-3000 auto-analyzer on admission and at subsequent time-points. IPF% on admission was higher in Covid-19 than the stable group and similar to the AMI group (4.8% [IQR 3.4-6.9], 3.5% [2.7-5.1], 4.55% [3.0-6.75], respectively, p = 0.0053). IPC on admission was also higher in Covid-19 than the stable group and similar to the
BackgroundThe “very late” clinical outcomes for durable polymer drug‐eluting stents and bare metal stents (BMSs) have been shown to be dissimilar in clinical studies. Conceptually, the long‐term vascular compatibility of BMSs is still regarded to be superior to drug‐eluting stents; however, no pathologic study to date has specifically addressed this issue. We evaluated the very late (≥1 year) pathologic responses to durable polymer drug‐eluting stents (cobalt–chromium [CoCr] everolimus‐eluting stents [EESs] and stainless steel sirolimus‐eluting stents [SS‐SESs]) versus BMSs (CoCr‐BMSs).Methods and ResultsFrom the CVPath stent registry, we studied a total of 119 lesions (40 CoCr‐EESs, 44 SS‐SESs, 35 CoCr‐BMSs) from 92 autopsy cases with a duration ranging from 1 to 5 years. Sections of stented coronary segments were pathologically analyzed. Inflammation score and the percentage of struts with giant cells were lowest in CoCr‐EESs (median inflammation score: 0.6; median percentage of struts with giant cells: 3.8%) followed by CoCr‐BMSs (median inflammation score: 1.3 [P<0.01]; median percentage of struts with giant cells: 8.9% [P=0.02]) and SS‐SESs (median inflammation score: 1.7 [P<0.01]; median percentage of struts with giant cells: 15.3% [P<0.01]). Polymer delamination was observed exclusively in SS‐SESs and was associated with increased inflammatory and giant cell reactions. The prevalence of neoatherosclerosis with CoCr‐EESs (50%) was significantly less than with SS‐SESs (77%, P=0.02) but significantly greater than with CoCr‐BMSs (20%, P<0.01).ConclusionsCoCr‐EESs, SS‐SESs, and BMSs each demonstrated distinct vascular responses. CoCr‐EESs demonstrated the least inflammation, near‐equivalent healing to BMSs, and lower neointimal formation. These results challenge the belief that BMSs have superior biocompatibility compared with some polymeric coated drug‐eluting stents and may have implications for future stent design.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.